Evaluation of the “Steal” Phenomenon on the Efficacy of Hypoxia Activated Prodrug TH-302 in Pancreatic Cancer

Abstract

Pancreatic ductal adenocarcinomas are desmoplastic and hypoxic, both of which are associated with poor prognosis. Hypoxia-activated prodrugs (HAPs) are specifically activated in hypoxic environments to release cytotoxic or cytostatic effectors. TH-302 is a HAP that is currently being evaluated in a Phase III clinical trial in pancreatic cancer. Using animal models, we show that tumor hypoxia can be exacerbated using a vasodilator, hydralazine, improving TH-302 efficacy. Hydralazine reduces tumor blood flow through the “steal” phenomenon, in which atonal immature tumor vasculature fails to dilate in coordination with normal vasculature. We show that MIA PaCa-2 tumors exhibit a “steal” effect in response to hydralazine, resulting in decreased tumor blood flow and subsequent tumor pH reduction. The effect is not observed in SU.86.86 tumors with mature tumor vasculature, as measured by CD31 and smooth muscle actin (SMA) immunohistochemistry staining. Combination therapy of hydralazine and TH-302 resulted in a reduction in MIA PaCa-2 tumor volume growth after 18 days of treatment. These studies support a combination mechanism of action for TH-302 with a vasodilator that transiently increases tumor hypoxia.

Distinguishing Closely Related Pancreatic Cancer Subtypes In Vivo by 13C Glucose MRI without Hyperpolarization

“…Beyond the Warburg effect, researchers have begun to target other vulnerable aspects of PDAC metabolism such as amino acid synthesis 44 or the unique chemical environment of tumors by hypoxia activated prodrugs. 2,45 Targeting aberrant metabolism requires a method of monitoring treatment progress and selecting suitable patient populations. Response to cancer treatment can be highly variable and there is a concerted push to tailor treatment regimes to individual patients.…”

“…21 As noted in previous reports, 2 we found similar levels of CD31, a common biomarker for angiogenesis ( Fig S1), 22 suggesting immature, rather than deficient, vasculature may be responsible for the higher hypoxia levels in Hs766t. 2 At the cellular level, cell rupture and inflammation were evident in Hs766t but not in MiaPaCa-2 cells (Figs. 1B and D arrows).…”

Hypoxia in cancer chemo- and immunotherapy: foe or friend?

“…The advection part is calculated by the regularized Stokeslets method (Eqs. 3,4). A movement of an individual T cell is governed by a combination of forces (Eq.5): a random migration drag force (Eq.6) and a passive repulsive force that prevents the cell from overlapping with other T cells and tumor cells (Eqs.7).…”

“…However, the clinical efficacy of these drugs could be improved by acutely exacerbating tumor hypoxia to increase the area and time window of HAP activity. Here, we consider two previously tested compounds, namely a vasodilator that temporarily decreases blood (and oxygen) flow to the tumor vasculature [4] and a metabolic sensitizer that increases oxygen consumption by the cells exposed to high concentrations of it [5]. Using the micropharmacology model, microPKPD ( Figure 1A), we systematically tested the various combination schedules of HAP with a vasodilator alone, sensitizer alone, and both compounds together for identifying the most effective protocols.…”

Value of combining dynamic contrast enhanced ultrasound and optoacoustic tomography for hypoxia imaging

“…Two pancreatic tumour models were chosen because they possess a heterogeneous vasculature with hypoxic regions [38] , [39] , [40] . The cell line, PDA-KPC-1 GEMM, derived from KPC mice, a genetically engineered pancreatic ductal adenocarcinoma model, was obtained from the University of Pennsylvania (Philadelphia, USA) [41] .…”